Advances in Targeted Therapy for R/R CLL - Episode 1

Chronic Lymphocytic Leukemia Treatment Landscape

Nicole Lamanna, MD, and Nirav N. Shah, MD, discuss the chronic lymphocytic leukemia treatment (CLL) landscape, including risk factors and treatment options.

Nirav N. Shah, MD: The question is to discuss the landscape of CLL [chronic lymphocytic leukemia] is in the era with all our new therapies. When you first see a patient with CLL, the basic question still remains: to treat or not to treat? That still isn’t necessarily impacted by prognostic markers. If a patient is asymptomatic, has normal blood counts, and has lymphadenopathy, there’s not enough significance to want treatment. A lot of patients can be observed, but we want to prognosticate them and perform a variety of tests. We do a CLL FISH [fluorescence in situ hybridization] panel to look for specific alterations, like an 11q deletion or a p53 deletion. Some people are saying we should be getting a TP53 mutational profile on all patients with CLL because it can be prognostic independent of having a deletion as well. We also want to check the IGHV mutational status. There’s another marker for patients who are more likely to respond to chemoimmunotherapy, which are those who are IGHV mutated, but that’s being challenged with some of the new frontline regimens available.

When I meet a patient with CLL, I try to get all that baseline information. I then evaluate them and determine whether they need treatment right now. If they do, we go through the various frontline options available, which consist of many good and reasonable options. I also try to get the patient’s chromosomes or the cytogenetics, which also have some prognostic value. Assuming a patient needs treatment, there are varying frontline options. For many people, treatments have fallen out of favor. Chemoimmunotherapy with FCR [fludarabine, cyclophosphamide, rituximab] can be considered in a young, healthy patient who is IGHV mutated. This is because we know that this population has a very favorable prognosis, even at 10 years after getting chemoimmunotherapy. There are adverse effects with chemotherapy and secondary malignancies. With newly tested agents that come head-to-head against chemoimmunotherapy, the overall field is moving toward novel agent therapy.

In the front line, there are 2 major classes of options. Those are going to be BTK [Bruton tyrosine kinase] inhibitor–based therapy or BCL2 inhibitor–based therapy. The BTK inhibitors include acalabrutinib and ibrutinib, which have been approved in the front line. Ibrutinib was the first BTK approved in CLL. It’s incredibly effective, and it has been tested in large randomized trials against chemoimmunotherapy.The findings favored ibrutinib as a single agent or in combination with rituximab. That’s the standard of care. However, there are now second-generation BTK inhibitors like acalabrutinib, which from an efficacy standpoint, look to be just as good as ibrutinib. But the toxicity profile of these more targeted agents, which have fewer off-target toxicities, does suggest perhaps less cardiovascular risk with drugs like acalabrutinib. This means less atrial fibrillation, fewer bleeding complications perhaps, and fewer long-term cardiovascular issues like hypertension. Acalabrutinib is also approved in the frontline setting and is part of many good options out there.

You have to think about your patient. What is their baseline medical issues? If they have a lot of cardiac history, maybe acalabrutinib is the better agent in that setting. I try to individualize the treatment approach to the patient’s needs. The other option that’s gaining a lot of excitement is fixed-duration treatment regimen: using a BCL2 inhibitor like venetoclax in combination with the CD20 antibody. This was studied in the CLL14 trial, and it showed that a fixed-duration combination of this regimen is efficacious and produces long-term progression-free survival [PFS]. This gives people an opportunity to be off treatment. This is different from BTK inhibitors, which are a continuous therapy until patients progress. The data with this combination is less mature than with the BTK inhibitors given that venetoclax came around later. Additionally, some of these newer fixed-duration regimens don’t have the same amount of follow-up. There are some concerns in the highest-risk patients, such as those with the p53 deletion or mutation, as to whether a fixed-duration approach is the best way to go. Those are the options right now. In the future, we’re going to be looking at combinations of BTK inhibitors with BCL2 inhibitors in a fixed-duration approach. This is almost like CML [chronic myelocytic leukemia], where you treat people for a period of time and then use things like minimal residual disease assays as a guide for when to stop treatment. The future of CLL is incredibly exciting. In the front line, we have many options. It’s a conversation with the patient while considering their prognostic markers. Trying to make a decision about the most efficacious agent with the best toxicity profile that fits your particular patient is key.

Nicole Lamanna, MD: We’re very fortunate when we look at a patient with CLL who was on active observation and now needs their initial treatment. Fortunately, we have many options of therapy. Traditionally we’ve used a lot of chemoimmunotherapy regimens like fludarabine, cyclophosphamide and rituximab, or bendamustine and rituximab, which may depend on where somebody may have lived. Particularly in Europe, a lot of chlorambucil and CD20 monoclonal antibodies were used traditionally. We’ve moved away from a lot of chemoimmunotherapy, given that we have the BCL receptor pathway agents and the BCL2 inhibitor venetoclax. We have ibrutinib and acalabrutinib approved, as well as venetoclax and obinutuzumab in frontline therapy. It’s not that I’ll never have the conversation about chemoimmunotherapy, but typically they’re going to be younger and fitter and have favorable disease characteristics like mutated IGHV or a 13q deletion. Then I’ll have that discussion, because we know from some long-term data from [The University of Texas] MD Anderson [Cancer Center] that a small cohort, about 20%, of those favorable patients are in long-term remission after FCR [fludarabine, cyclophosphamide, rituximab]. That’s a time-limited therapy. Because there are adverse effects, it’s rare that many of my younger and fitter patients in that favorable category will choose chemoimmunotherapy, given these other options.

We have great options with ibrutinib or acalabrutinib as the BTK inhibitors and venetoclax and obinutuzumab, which is a time-limited approach as well. The decision to choose among the BTK inhibitors and venetoclax-obinutuzumab will be based on patient preferences and disease characteristics. If somebody is high risk—17p or a TP53 mutation—I’ll still favor a BTK monotherapy based on the data we have. The PFS looks very good for continuous therapy, and we have the longest follow-up for that. We’ll need more follow-up on venetoclax-obinutuzumab, or the time-limited therapies in our high-risk individuals. Oftentimes, I’ll choose a BTK inhibitor in that sense and then look at patient comorbidities. If somebody has terribly controlled hypertension or cardiac issues, then I’ll consider a second-generation BTK inhibitor or choose venetoclax-obinutuzumab in that sense. If somebody has terrible renal function, then of course I’m considering a BTK inhibitor.

There are options of therapy, and you can fine-tune and tailor those options depending on their comorbidities, disease characteristics, and preference. Obviously, it’s easy to start a BTK inhibitor and monitor them. It’s not very labor-intensive, and it’s especially favorable during COVID-19, when you don’t want to bring back and forth patients who need a lot of monitoring. For tumor lysis patients based on the venetoclax combinations, you do need to monitor them and have them come frequently to monitor their laboratory values, particularly during that 5-week ramp-up. Depending upon what’s going on in your region, that may not be suitable during the time period. There are lots of options you can pick from. These are great therapies for someone’s disease, and there are many more options than we had in the era of chemoimmunotherapy.

This transcript has been edited for clarity.